Mukaiyama aldol - Prins cyclization cascade reaction: A formal total synthesis of leucascandrolide A [1]

Full text of DOI:10.1021/ja011377n

8420
J. Am. Chem. Soc. 2001, 123, 8420-8421
Mukaiyama Aldol-Prins Cyclization Cascade
Reaction: A Formal Total Synthesis of
Leucascandrolide A
David J. Kopecky and Scott D. Rychnovsky*
Department of Chemistry, UniVersity of California
IrVine, California 92697-2025
ReceiVed June 5, 2001
Cascade reactions, in which the reactive intermediate from one
step directly undergoes further transformations, are important in
organic synthesis because they can build up molecular complexity
very rapidly.1 We have developed a new cascade reaction, a
Mukaiyama aldol coupling followed by a Prins cyclization,2 and
illustrate the potential of this new reaction with a synthesis of
the leucascandrolide A macrolide.
Figure 1. Conceptualization of the aldol-Prins reaction to avoid
oligomerization in the reaction of electrophiles with alkyl enol ethers.
Table 1. Aldol-Prins Cyclizations with Simple Aldehydesa
Electrophilic additions to alkyl enol ethers are often problematic
because the intermediate oxocarbenium ion, for example, 3, is a
very reactive electrophile and can react with the starting enol ether
to produce oligomers, Figure 1. We sought to avoid this side
reaction by introducing a nucleophile into the enol ether that
would trap the oxocarbenium ion, for example, 4, and produce a
new ring. Where the internal nucleophile is an alkene, the trapping
reaction becomes a Prins cyclization. The alkene must be reactive
enough to prevent polymerization of the enol ether.
Initial studies with terminal alkenes as intramolecular nucleo-
philes only partially suppressed the competing polymerization
reactions.3 The use of a more reactive alkene, the allylsilane 6,
completely eliminated polymerization. The cyclization of 6 can
be promoted by a variety of electrophiles, including a proton, eq
1. Aldehyde electrophiles reacted with enol 6 in the presence of
a Lewis acid, but protonation and cyclization was competitive.
The protonation reaction was suppressed by the addition of 2,6-
di-tert-butylpyridine.
a Aldol-Prins cyclizations were run using 2.5 equiv of BF3‚OEt2,
2.5 equiv of aldehyde and 1.5 equiv of 2,6-di-tert-butylpyridine.
b Product yields are after chromatography. c Diastereomeric ratios were
based on isolated yields or 1H NMR analysis. d 2.0 equiv of BF3‚OEt2,
1.2 equiv of isobutyraldehyde and 1.2 equiv of 2,6-di-tert-butylpyridine
were used.
The aldol-Prins reactions of enol allylsilanes with a variety
of aldehydes are listed in Table 1.4 The yields ranged from good
to excellent, and the cis-2,6-disubstituted tetrahydropyran products
were formed stereoselectively. The aldol-Prins reaction worked
well with aliphatic, aromatic, R,â-unsaturated, and oxygen-
substituted aldehydes. The facial selectivity in the addition to the
aldehyde, however, was minimal, as might be expected consider-
ing the distance between the reactive end of the enol and the
stereogenic center in 6 and 21. The advantage of this minimal
facial selectivity is that there is no mismatched case when using
other elements to control the aldehyde selectivity. Two obvious
methods for introducing facial selectivity in the aldehyde com-
ponent are the use of a chiral Lewis acid and the use of a chiral
aldehyde. We develop the latter strategy in an approach to the
natural product leucascandrolide A.
cancer cells.5 It has attracted the interest of a number of synthetic
chemists, and the first total synthesis was recently reported by
the Leighton group.6,7 Our synthetic analysis identified aldehyde
17 and enol ether 21 as key building blocks that should undergo
aldol-Prins coupling to produce most of the leucascandrolide A
skeleton in a single step. The syntheses of 17 and 21 are illustrated
in Scheme 1, and their coupling and ultimate conversion to the
leucascandrolide A macrolide are outlined in Scheme 2.
Synthesis of the optically pure aldehyde 17 followed well-
established methods. Noyori hydrogenation8 of 14 introduced the
first stereogenic center with 94% ee. Protection, reduction, and
iodide formation gave the alkylating agent 15 in good yield.
Myers’ pseudoephedrine auxiliary9 was used to introduce the C12
stereocenter by alkylation of iodide 15, and acid treatment gave
Leucascandrolide A was isolated from the sponge Leucascan-
dra caVeolata in 1996 and shows potent cytotoxicity against P388
(1) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) The aldol-Prins reaction is related to other cationic annulations of enol
ethers: (a) Nussbaumer, C.; Frater, G. HelV. Chim. Acta 1987, 70, 396. (b)
Lee, T. V.; Boucher, R. J.; Porter, J. R.; Rockell, C. J. M. Tetrahedron 1989,
45, 5887. (c) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am. Chem.
Soc. 1998, 120, 1724. (d) Tanino, K.; Shimizu, T.; Miyama, M.; Kuwajima,
I. J. Am. Chem. Soc. 2000, 122, 6116.
(5) D’Ambrosio, M. D.; Guerriero, A.; Debitus, C.; Pietra, F. HelV. Chim.
Acta 1996, 79, 51.
(6) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc.
2000, 122, 12894.
(3) These studies were carried out by Dr. Bruce Ellsworth.
(4) Aldol-Prins optimization studies identified BF3‚OEt2 as the Lewis acid
of choice.
(7) (a) Crimmins, M. T.; Carroll, C. A.; King, B. W. Org. Lett. 2000, 2,
597. (b) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242. (c) Kozmin,
S. A. Org. Lett. 2001, 3, 755.
10.1021/ja011377n CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/22/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 34, 2001 8421
Scheme 1. Syntheses of the Aldol-Prins Precursors 17 and 21
Scheme 2. Aldol-Prins Coupling and Synthesis of the
of Leucascandrolide Aa
Leucascandrolide A Macrolidea
a (a) [(R)-BINAP]-RuCl(C6H6), 80 atm H2, EtOH, 96%, 94% ee; (b)
TBSCl, imidazole, DMF, 86%; (c) DIBALH, THF, -25 °C, 88%; (d)
PPh3, I2, imidazole, CH2Cl2, quant.; (e) combine LDA, (-)-pseudoephe-
drine propionamide, LiCl, then add 15, THF, -78 °C, 98%, g20:1 dr;
(f) 2N H2SO4, dioxane, 95 °C, 77%; (g) i. DIBALH, CH2Cl2, -78 °C,
ii. Ac2O, DMAP, pyridine, 95%; (h) Allyltrimethylsilane, BF3‚OEt2, CH2-
Cl2; -78 °C, 97%, g20:1 dr; (i) O3, CH2Cl2, -78 °C, then PPh3, 95%;
(j) N2CHCO2Et, SnCl2, CH2Cl2, 72%; (k) [(S)-BINAP]-RuCl(C6H6), 4
atm H2, EtOH, 100 °C, 51%, g95% ee; (l) TMSCl, Et3N, CH2Cl2, 91%;
(m) i. CeCl3, TMSCH2MgCl, THF/Et2O, -78 °C to 23 °C, ii. SiO2 gel,
CH2Cl2, 87% (n) ClCH2COCl, pyridine, CH2Cl2, 95%; (o) i. DIBALH,
CH2Cl2, -78 °C, ii. Ac2O, DMAP, pyridine, 95%; (p) Li°, NH3, THF,
-78 °C, 65%.
a (a) i. BF3‚OEt2, 2,6-di-tert-butylpyridine, CH2Cl2, -78 °C, ii. NaBH4,
EtOH, 78%, 5.5:1 dr at C9; (b) MeO+BF4-, Proton Sponge, 4 Å M.S.,
CH2Cl2, 79% (single epimer) plus C9 epimer (15%), (c) i. OsO4, NMO,
ii. NaIO4, 80%; (d) L-Selectride, THF, -90 to -60 °C, 82% (single
epimer) plus C5 epimer (10%); (e) TBAF, THF, 92%; (f) TBSOTf, 2,6-
lutidine, CH2Cl2, 89%; (g) H2, Pd(OH)2, EtOAc, 96%; (h) Swern, 94%;
(i) Me2AlCl, Me3SnCCCH2CH(CH3)2, PhCH3, -78 °C, 80%, 3.5:1 dr at
C17; (j) Red-Al, Et2O, 60% (single epimer) plus recovered SM and C17
epimer; (k) Ac2O, DMAP, pyridine, CH2Cl2, 89%; (l) Neutral Al2O3,
hexanes, 96%; (m) Swern, 97%; (n) NaClO2, NaH2PO4, 2-methyl-2-
butene, 71%; (o) i. K2CO3, MeOH, ii. Cl3C6H2COCl, Et3N, DMAP, C6H6,
23 °C, 56%; (p) HF‚pyridine, THF, 96%.
the lactone 16 with g20:1 selectivity. Reductive acetylation,10
axial allylation, and ozonolysis completed the synthesis of 17.
The synthesis of 21 was also straightforward. Noyori hydro-
genation of a â-keto ester generated the only stereogenic center
in the target with >94% ee. Bunnelle’s method11 was used to
convert the ester 19 to the 2-substituted allylsilane 20. The sensi-
tive enol ether was introduced using a new method: esterification
with chloroacetyl chloride, reductive acetylation,10 and elimination
of the acetate and chloride groups by Li/NH3 reduction. The enol
ether 21 was isolated in good overall yield. We will continue to
develop this promising new enol ether synthesis. With 17 and 21
in hand, the key aldol-Prins reaction could be investigated.
Aldehyde 17 and enol ether 21 were coupled using the same
conditions described in Table 1, BF3‚OEt2 and 2,6-di-tert-
butylpyridine at -78 °C, to give the product 22 as a 5.5:1 mixture
of epimers at C9 in 78% yield.12,13 The major epimer was shown
to have the desired (S)-configuration by advanced Mosher’s
analysis.14 The problematic methylation of C9 was carried out
with trimethyloxonium tetrafluoroborate and Proton Sponge, and
the C9 epimers were separated at this stage. Oxidative cleavage
of the alkene and L-Selectride reduction introduced the axial C5
alcohol, and reprotection gave 23. The C17 substituent was
introduced by a chelation-controlled alkynylstannane addition to
the corresponding aldehyde.15 The selectivity was 3.5:1, which
is slightly higher than what Leighton found using a diastereose-
lective alkenylzinc addition.6 Red-Al reduction gave the (E)-alkene
24. The minor C17 epimer was easily separated at this stage.
Reprotection and oxidation of the C1 alcohol gave the seco acid
ester 25. Hydrolysis, Yamaguchi-type cyclization,16 and desilyla-
tion completed the synthesis of the leucascandrolide A macrolide.
Synthetic leucascandrolide A macrolide showed 1H and 13C NMR
data that was identical to that provided by Professor Leighton.
The side chain of leucascandrolide A has been attached to the
macrolide in two steps,6 and thus our work constitutes a formal
total synthesis of leucascandrolide A.
The aldol-Prins reaction brings together an aldehyde and an
enol ether to form a new tetrahydropyran ring. The reaction is
successful with a variety of aldehydes, and its utility can be seen
in the synthesis of leucascandrolie A macrolide. We will continue
to explore the selectivity and scope of this new method.
Acknowledgment. Financial support was by the National Institutes
of Health (CA81635). Professor Lighton kindly provided 1H and 13C NMR
spectra for the leucascandrolide macrolide.
(8) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856.
(9) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L. M.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(10) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(11) (a) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
(b) Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990, 69, 89.
(12) The diastereoselectivity of the aldehyde addition arises from minimiza-
tion of steric and electronic interactions in the transition state, see: (a) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556. (b) Evans, D. A.; Dart, M.
J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
(13) Sodium borohydride was used to reduce unreacted 17 to facilitate
chromatographic purification of 22.
Supporting Information Available: Experimental procedures and
compound characterization for the work described (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA011377N
(15) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999,
40, 4461.
(16) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Sakurai, Y.; Horita, K.;
Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
(14) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.